The study of the pathogenesis of HIV, and the evaluation of intervention modalities, continues to be limited by the lack of a reliable small animal model of HIV infectivity. We propose to address this deficiency by utilizing genetically altered strains of NOD/LtSz-scid/scid mice to develop a relevant model for the study of HIV-1 infection in human lymphohematopoietic cells. This model will be used for the study of viral pathogenesis and intervention strategies, including in vivo evaluation of antibodies, antiviral drugs, and CTL. To accomplish our objective, we propose an integrated approach involving 3 laboratories with expertise in mammalian genetics, in lymphocyte development and function, and in HIV pathogenesis and therapy. Specific Aim #1 will evaluate the engraftment and immune function of human lymphocytes in new genetic stocks of NOD/LtSz-scid/scid mice. We have shown that the genetic background of the NOD/Lt mouse with defects in innate immunity allows improved engraftment and HIV infection of human PBMC in scid/scid mice. We will test the ability of NOD/LtSz-scid/scid mice deficient in NK cell activity, MHC class I, and MHC class II antigens to support engraftment with human lymphocytes and to generate primary and secondary immune responses. Specific Aim #2 will determine levels of HIV infection and pathogenesis in human lymphohematopoietic cell engrafted NOD/LtSz-scid/scid mice. Studies of HIV infection in these mice will include evaluation of virus load, and effects of different viral phenotypes on engrafted cells. Rapidly growing cytopathic viruses, slow-growing viruses with low cytopathic potential, and primary viral isolates obtained from long-term nonprogressors with novel genetic defects will be tested. Infection with nef-deleted viruses on immature and mature human lymphocytes will be studied. Specific Aim #3 is to evaluate therapeutic modalities aimed at preventing or interrupting HIV-1 replication in human lymphocyte engrafted NOD/LtSz-scid/scid mice. We will evaluate interruption of HIV-l replication using anti-retroviral therapies (AZT, Nevirapine, etc.), HIV-1 specific antibodies, and HIV-1 specific cytotoxic T cells. Accomplishment of the work in this proposal will provide a reliable small animal model system that allows the rapid evaluation of HIV therapeutics, vaccines, and gene therapy for studies aimed at interrupting HIV- 1 pathogenesis.